EP0966276B1 - Verwendung von beta-3-adrenorezeptoragonisten zur herstellung von wundheilmitteln - Google Patents

Verwendung von beta-3-adrenorezeptoragonisten zur herstellung von wundheilmitteln Download PDF

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Publication number
EP0966276B1
EP0966276B1 EP98903099A EP98903099A EP0966276B1 EP 0966276 B1 EP0966276 B1 EP 0966276B1 EP 98903099 A EP98903099 A EP 98903099A EP 98903099 A EP98903099 A EP 98903099A EP 0966276 B1 EP0966276 B1 EP 0966276B1
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Prior art keywords
group
alkyl
tetrahydronaphth
defined above
substituted
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EP98903099A
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French (fr)
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EP0966276A1 (de
Inventor
André Bernat
Jean-Marc Herbert
Michèle Arnone
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Sanofi Aventis France
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Sanofi Synthelabo SA
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention relates to a new indication for agonists of beta-3 adrenergic receptors.
  • the invention relates to the use of agonists of beta-3 adrenergic receptors for the preparation of wound healing drugs.
  • beta-3 adrenergic receptor agonists are likely to be used for the treatment of obesity and diabetes, although the clinical evidence of this activity has not been provided with certainty.
  • ⁇ 3 -agonists beta-3 adrenergic receptors
  • IBD inflammatory bowel disease
  • irritable bowel syndrome a non-steroidal anti-inflammatory drugs
  • ⁇ 3 -agonists includes compounds that are beta receptor agonists that have been defined as “atypical” or “non ⁇ 1 non ⁇ 2 " and which are now recognized as an adrenergic receptor subtype called " ⁇ 3 ".
  • Treating unhealed wounds is a clinical problem serious, difficult to resolve because healing wounds involves a complex series of phenomena which are superimposed and which are difficult to master in their entirety.
  • fibroblast growth factor basic fibroblast growth factor basic
  • aFGF factor of acid fibroblases
  • sphingosylphosphorylcholine J. Invest. Dermatol., 1996, 106, 232-237
  • ⁇ 3 -agonists act by accelerating the healing of dermal wounds in diabetic mammals.
  • the present invention relates to the use of ⁇ 3 -agonists for the preparation of healing drugs.
  • the activity of the compounds was demonstrated using a scar measurement test after creating a skin lesion of 1 cm 2 on the back of mice by removing a skin fragment.
  • Diabetic animals were subjected to the ⁇ 3 -agonist versus placebo study.
  • the compound was administered orally at 10 mg / kg.
  • Healing was assessed by measuring the area of the lesion daily in treated animals and in those receiving placebo.
  • the ⁇ 3 -agonist compounds may well be used in the prophylaxis and / or the treatment of dermal wounds, in particular in the prophylaxis and / or the treatment of lower extremity wounds in diabetic mammals.
  • the present invention relates to the use of a prophylactic and / or effective amount of a ⁇ 3 -agonist compound for the preparation of medicaments for the prophylaxis and / or treatment of injuries, in particular in diabetic mammals.
  • the subject of the present invention is the use of a prophylactic and / or effective amount of a compound chosen from the compounds of formula (I), (II) and (III) for the preparation of medicaments for the prophylaxis and / or treatment of injuries, especially in mammals diabetics.
  • the amount of active ingredient to be administered in the treatment of injuries according to the present invention depends on the nature and severity of the conditions to be treated as well than the potency of the compound and the weight of the patients. Generally the dose is between 0.01 and 30 mg per kg of body weight, preferably between 0.1 and 20 mg per kg of body weight, especially between 1 and 10 mg per kg of body weight.
  • the active ingredient is formulated in dosage units containing from 0.1 to 400 mg, and preferably from 0.5 to 200 mg of active ingredient in combination with a pharmaceutical carrier.
  • the dosage unit depends on the severity and the extension of injuries as well as the concentration of active ingredient in the pharmaceutical formulation.
  • a cream, an ointment, a gel containing from 0.01 to 5%, advantageously from 0.025 to 2.5%, preferably from 0.1 to 1% of ⁇ 3 -agonist is mixed in mixture with the usual excipients. for topical application.
  • a lotion or, in general, a solution or a suspension in which the ⁇ 3 -agonist is present at concentrations of 0.0001 to 1% It is also possible to use a lotion or, in general, a solution or a suspension in which the ⁇ 3 -agonist is present at concentrations of 0.0001 to 1%.
  • the active ingredient can be administered in the form administration units, either as is, for example in lyophilized form, or in mixture with conventional pharmaceutical carriers, animals and beings humans for the treatment of the above conditions.
  • Unit forms suitable administration forms include oral forms such as possibly scored tablets, capsules, powders, granules and oral solutions or suspensions, forms of sublingual and oral administration, subcutaneous, intramuscular or intravenous administration forms, forms of local administration and forms of rectal administration.
  • a solid composition in the form of tablets When preparing a solid composition in the form of tablets, it is mixed the main active ingredient with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or like.
  • a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or like.
  • a preparation in capsules is obtained by mixing the active ingredient with a diluting and pouring the mixture obtained into soft or hard capsules.
  • a preparation in the form of syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a color appropriate.
  • a sweetener preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a color appropriate.
  • Water dispersible powders or granules may contain the ingredient active in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or flavor correctors.
  • Suppositories are used for rectal administration. with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
  • aqueous suspensions, saline or sterile and injectable solutions that contain pharmacologically compatible dispersion and / or wetting agents, for example propylene glycol or butylene glycol.
  • the active principle can also be formulated in the form of microcapsules, possibly with one or more carriers or additives.
  • the active ingredient is mixed in an excipient for preparing lotions, gels, creams or ointments or dissolving it in a timely vehicle.
  • the principle active can also be in the form of inclusion complex in cyclodextrins, their ethers or their esters.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Claims (11)

  1. Verwendung von β3-Agonisten zur Herstellung von Wundheilmitteln.
  2. Verwendung nach Anspruch 1 zur Herstellung von pharmazeutischen Zusammensetzungen, die dazu vorgesehen sind, die Heilung von Wunden der unteren Gliedmaßen bei diabetischen Säugern zu beschleunigen.
  3. Verwendung nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass es sich bei dem β3-Agonisten um eine Verbindung der Formel (I):
    Figure 00160001
    worin bedeuten:
    X
    Wasserstoff, Halogen, Trifluormethyl oder C1-4-Alkyl; und
    R
    Wasserstoff oder eine Methylgruppe, die unsubstituiert oder mit einer Carboxygruppe oder Methoxy- oder Ethoxycarbonylgruppe substituiert ist;
    oder ein pharmazeutisch akzeptables Salz dieser Verbindungen handelt.
  4. Verwendung nach Anspruch 3, dadurch gekennzeichnet, dass der β3-Agonist unter den folgenden Verbindungen ausgewählt ist:
    2-[(7-Hydroxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-phenylethanol;
    2-[(7-Hydroxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-(3-chlorphenyl)ethanol;
    2-[(7-Carbethoxymethoxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-(3-chlorphenyl)ethanol;
    2-[(7-Carbethoxymethoxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-phenylethanol;
    (1R,2'RS)-2-[(7-Hydroxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-phenylethanol;
    (1S,2'RS)-2-[(7-Hydroxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-phenylethanol;
    (+)-(1R)-2-[(7-Hydroxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-phenylethanol;
    (+)-(1S)-2-[(7-Hydroxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-phenylethanol;
    (-)-(1R)-2-[(7-Hydroxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-phenylethanol;
    (-)-(1S)-2-[(7-Hydroxy-1,2,3,4-tetrahydronapht-2-yl)amino]-1-phenylethanol;
    N-[(2R)-7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydronapht-2-yl]-(2R)-2-(3-chlorphenyl)-2-hydroxyethanamin;
    N-[(2R)-7-Methoxycarbonylmethoxy-1,2,3,4-tetrahydronapht-2-yl]-(2R)-2-(3-chlorphenyl)-2-hydroxyethanamin;
    N-[(2S)-7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydronapht-2-yl]-(2R)-2-(3-chlorphenyl)-2-hydroxyethanamin;
    und deren pharmazeutisch akzeptablen Salzen.
  5. Verwendung nach Anspruch 3, dadurch gekennzeichnet, dass der β3-Agonist das N-[(2R)-7-Ethoxycarbonylmethoxy-1,2,3,4-tetrahydronapht-2-yl]-(2R)-2-(3-chlorphenyl)-2-hydroxyethanamin oder ein pharmazeutisch akzeptables Salz dieser Verbindung ist.
  6. Verwendung nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass der β3-Agonist eine Verbindung der folgenden Formel (II) ist:
    Figure 00180001
    worin bedeuten:
    n
    1, 2 oder 3;
    A
    Benzofuran-2-yl oder eine Phenylgruppe, die unsubstituiert vorliegt oder mit einem oder zwei Halogenatomen oder einer C1-4-Alkylgruppe oder Trifluormethylgruppe substituiert ist;
    R'
    • Wasserstoff;
    • C1-6-Alkyl;
    • eine funktionelle Gruppe, die unter den folgenden Gruppen ausgewählt ist: Hydroxy; C1-6-Alkoxy; C2-6-Alkenyloxy; C2-6-Alkinyloxy; C3-8-Cycloalkyloxy; C3-8-Cycloalkyl-C1-6-alkoxy; Benzyloxy; Phenoxy; Mercapto; C1-6-Alkylthio; C2-6-Alkenylthio; C2-6-Alkinylthio; C3-8-Cycloalkylthio; C3-8-Cycloalkyl-C1-6-alkylthio; Benzylthio; Phenylthio; (C1-6-Alkyl)sulfinyl; (C2-6-Alkenyl)sulfinyl; (C2-6-Alkinyl)sulfinyl; C3-8-Cycloalkylsulfinyl; (C3-8-Cycloalkyl-C1-6-alkyl)sulfinyl; Benzylsulfinyl; Phenylsulfinyl; (C1-6-Alkyl)sulfonyl; (C2-6-Alkenyl)sulfonyl; (C2-6-Alkinyl)-sulfonyl; C3-8-Cycloalkylsulfonyl; (C3-8-Cycloalkyl-C1-6-alkyl)sulfonyl; Benzylsulfonyl; Phenylsulfonyl; Cyano; Nitro; eine Aminogruppe, die unsubstituiert vorliegt oder mit einer oder zwei Gruppen substituiert ist, die gleich oder verschieden sind und unter C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-8-Cycloalkyl, C3-8-Cycloalkyl-C1-6-alkyl, Benzyl oder Phenyl ausgewählt sind; Carboxy, Carbalkoxy, dessen Alkylgruppe 1 bis 6 Kohlenstoffatome enthält; (C2-6-Alkenyloxy)carbonyl; (C2-6-Alkinyloxy)carbonyl; (C3-8-Cycloalkyloxy)carbonyl; (C3-8-Cycloalkyl-C1-6-alkoxy)-carbonyl; Benzyloxycarbonyl; Phenoxycarbonyl; Carbamoyl, das unsubstituiert vorliegt oder an der Aminogruppe mit einer oder zwei Gruppen substituiert ist, die gleich oder verschieden sind und unter C1-6-Alkyl, C2-6-Alkenyl, C2-6-Alkinyl, C3-8-Cycloalkyl, C3-8-Cycloalkyl-C1-6-alkyl, Benzyl und Phenyl ausgewählt sind;
    • eine Gruppe R'", die unter den mit einer funktionellen Gruppe substituierten C1-6-Alkylgruppen; den mit einer funktionellen Gruppe substituierten C2-6-Alkenylgruppen; den mit einer funktionellen Gruppe substituierten C2-6-Alkinylgruppen; den an der Phenylgruppe mit einer C1-6-Alkylgruppe oder einer funktionellen Gruppe substituierten Phenyl-C1-6-alkylgruppen; den an der Phenylgruppe mit einer C1-6-Alkylgruppe oder einer funktionellen Gruppe substituierten Phenyl-C2-6-alkenylgruppen; den an der Phenylgruppe mit einer C1-6-Alkylgruppe oder einer funktionellen Gruppe substituierten Phenyl-C2-6-alkinylgruppen; den mit einer C1-6-Alkylgruppe oder einer funktionellen Gruppe substituierten Benzylgruppen; und einer unsubstituierten Phenylgruppe oder mit einer C1-6-Alkylgruppe oder einer funktionellen Gruppe substituierten Phenylgruppen ausgewählt ist; wobei die funktionelle Gruppe die oben für R' angegebenen Bedeutungen aufweist;
    • eine Gruppe O-R'", S-R'", SO-R'", SO2R'", wobei R'" die oben für R' angegebenen Bedeutungen aufweist;
    • eine Gruppe NR'"R0, wobei R'" die oben angegebenen Bedeutungen aufweist und R0 Wasserstoff bedeutet oder die für R'" angegebenen Bedeutungen aufweist, oder R'" und R0 bilden gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, eine Gruppe, die unter den Gruppen Pyrrolidino, Piperidino und Morpholino ausgewählt ist;
    • eine Gruppe COOR'" oder eine Gruppe CO-SR"', wobei R'" die oben angegebenen Bedeutungen aufweist;
    • eine Gruppe CONR'"R0, wobei R'" die oben angegebenen Bedeutungen aufweist und R0 Wasserstoff bedeutet oder die oben für R'" angegebenen Bedeutungen aufweist, oder R'" und R0 bilden gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, eine Gruppe, die unter den Gruppen Pyrrolidino, Piperidino und Morpholino ausgewählt ist;
    • eine Gruppe SO2NR'"R0, wobei R'" die oben angegebenen Bedeutungen aufweist und R0 Wasserstoff bedeutet oder die oben für R'" angegebenen Bedeutungen aufweist, oder R'" und R0 bilden gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, eine Gruppe, die unter den Gruppen Pyrrolidino, Piperidino und Morpholino ausgewählt ist;
    R"
    • Wasserstoff;
    • Halogen;
    • C1-6-Alkyl;
    • eine funktionelle Gruppe, wie sie oben für R' definiert wurde;
    • eine Gruppe OR'", wobei R'" die oben angegebenen Bedeutungen aufweist;
    • eine Gruppe COOR'", wobei R'" die oben angegebenen Bedeutungen aufweist;
    • eine Gruppe CONR'"R0, wobei R'" die oben angegebenen Bedeutungen aufweist und R0 Wasserstoff bedeutet oder die oben für R'" angegebenen Bedeutungen aufweist, oder R'" und R0 bilden gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, eine Gruppe, die unter den Gruppen Pyrrolidino, Piperidino und Morpholino ausgewählt ist;
    W
    eine direkte Bindung oder ein Sauerstoffatom;
    X'
    Wasserstoff, C1-6-Alkyl oder C1-6-Alkylcarbonyl;
    Y
    Wasserstoff oder eine Gruppe A'-CH(OH)-CH2-, wobei A' mit A identisch, jedoch von Benzofuran-2-yl verschieden ist; oder
    X' und Y
    bilden gemeinsam eine Methylengruppe, die gegebenenfalls mit einer Carbalkoxygruppe substituiert ist, deren Alkylgruppe 1 bis 6 Kohlenstoffatome aufweist; eine Ethylengruppe, die gegebenenfalls mit einer Oxogruppe substituiert ist; oder eine 1,3-Propylengruppe; und
    Z
    Wasserstoff oder C1-6-Alkyl;
    oder ein pharmazeutisch akzeptables Salz dieser Verbindungen.
  7. Verwendung nach einem der Ansprüche 1 oder 2, dadurch gekennzeichnet, dass der β3-Agonist eine Verbindung der folgenden Formel (III) ist:
    Figure 00220001
    worin bedeuten:
    E
    Wasserstoff, C1-4-Alkyl, C1-4-Alkoxy, Phenyl, Nitro, Halogen oder Trifluormethyl,
    L
    Wasserstoff, C1-4-Alkyl, C1-4-Alkoxy, Phenyl, Nitro oder Halogen, oder
    E
    und L bedeuten gemeinsam eine Gruppe -CH=CH-CH=CH- oder -CH2-CH2-CH2-CH2-, und
    G
    Wasserstoff, Chlor, Hydroxy oder eine Gruppe OG', wobei G' eine unsubstituierte C1-4-Alkylgruppe oder eine C1-4-Alkylgruppe ist, die mit einer Hydroxygruppe, C1-4-Alkoxy, C1-4-Alkoxycarbonyl, Carboxy oder C3-7-Cycloalkyl substituiert ist; C3-7-Cycloalkyl; C2-4-Alkanoyl,
    oder ein pharmazeutisch akzeptables Salz dieser Verbindungen.
  8. Verwendung nach Anspruch 7, dadurch gekennzeichnet, dass der β3-Agonist unter N-[(6-Hydroxy-1,2,3,4-tetrahydronaphthalin-(2R)-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorphenyl)-ethanamin, N-[(7-Methoxy-1,2,3,4-tetrahydronaphthalin-(2R)-2-yl)methyl]-(2R)-2-hydroxy-2-(3-chlorphenyl)ethanamin und deren pharmazeutisch akzeptablen Salzen ausgewählt ist.
  9. Pharmazeutische Zusammensetzung zur lokalen Verabreichung, dadurch gekennzeichnet, dass sie 0,01 bis 5 % eines β3-Agonisten als Wirkstoff enthält.
  10. Pharmazeutische Zusammensetzung nach Anspruch 9, dadurch gekennzeichnet, dass sie 0,025 bis 2,5 % Wirkstoff enthält.
  11. Pharmazeutische Zusammensetzung nach Anspruch 10, dadurch gekennzeichnet, dass sie 0,1 bis 1 % Wirkstoff enthält.
EP98903099A 1997-01-21 1998-01-21 Verwendung von beta-3-adrenorezeptoragonisten zur herstellung von wundheilmitteln Expired - Lifetime EP0966276B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9700584 1997-01-21
FR9700584A FR2758460B1 (fr) 1997-01-21 1997-01-21 Utilisation des agonistes des recepteurs beta-3 adrenergiques pour la preparation de medicaments cicatrisants
PCT/FR1998/000105 WO1998031357A1 (fr) 1997-01-21 1998-01-21 Utilisation des agonistes des recepteurs beta-3 adrenergiques pour la preparation de medicaments cicatrisants

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EP0966276A1 EP0966276A1 (de) 1999-12-29
EP0966276B1 true EP0966276B1 (de) 2003-12-10

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US (1) US6235793B1 (de)
EP (1) EP0966276B1 (de)
JP (1) JP2001508790A (de)
AR (1) AR011546A1 (de)
AT (1) ATE255889T1 (de)
AU (1) AU5994198A (de)
BR (1) BR9807288A (de)
CA (1) CA2278220A1 (de)
DE (1) DE69820422T2 (de)
FR (1) FR2758460B1 (de)
HR (1) HRP980023A2 (de)
NO (1) NO326823B1 (de)
UY (1) UY24848A1 (de)
WO (1) WO1998031357A1 (de)
ZA (1) ZA98484B (de)

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FR2817257B1 (fr) 2000-11-30 2009-03-20 Sanofi Synthelabo Cyclohexyl(alkyl)-propanolamines, leur preparation et compositions pharmaceutiques en contenant
AU2003242250A1 (en) * 2002-06-12 2003-12-31 Sumitomo Pharmaceuticals Co., Ltd. Cyclic amine and medicinal composition containing the same
US8474489B2 (en) 2006-12-22 2013-07-02 National Oilwell Varco Denmark Flexible pipe
BRPI0720558B1 (pt) 2006-12-22 2018-10-23 National Oilwell Varco Denmark I/S tubo flexível
WO2022174309A1 (en) * 2021-02-22 2022-08-25 The University Of Sydney Wound healing methods

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DE3070865D1 (en) * 1979-11-15 1985-08-14 Beecham Group Plc Secondary ethanol amines, their preparation and their use in pharmaceutical compositions
GB8528633D0 (en) * 1985-11-21 1985-12-24 Beecham Group Plc Compounds
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US5578638A (en) * 1993-11-05 1996-11-26 American Cyanamid Company Treatment of glaucoma and ocular hypertension with β3 -adrenergic agonists
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US6235793B1 (en) 2001-05-22
ATE255889T1 (de) 2003-12-15
AU5994198A (en) 1998-08-07
CA2278220A1 (en) 1998-07-23
BR9807288A (pt) 2000-03-21
HRP980023A2 (en) 1998-10-31
JP2001508790A (ja) 2001-07-03
DE69820422T2 (de) 2004-10-28
NO993548D0 (no) 1999-07-20
FR2758460A1 (fr) 1998-07-24
UY24848A1 (es) 1998-04-21
ZA98484B (en) 1998-07-30
WO1998031357A1 (fr) 1998-07-23
DE69820422D1 (de) 2004-01-22
NO993548L (no) 1999-07-20
AR011546A1 (es) 2000-08-30
FR2758460B1 (fr) 1999-12-31
EP0966276A1 (de) 1999-12-29
NO326823B1 (no) 2009-02-23

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